DE2410492A1 - NEW BORNAND DERIVATIVES, THE PROCESS FOR THEIR PRODUCTION AND THEIR USE - Google Patents

Description

. TELEPHONE: COLLECTIVE NO. 2253 41

CHECK ACCOUNT: MUNICH 91139-809, BLZ 7001008O

BANK ACCOUNT: BANKHAUS H. AUFHÄUSER ACCOUNT NO. 397997. BLZ 70030600

8 MUNICH 2.

53 / My
Antivirais 21/22

GMXO LABORATORIES LIMITED, Greenford, Middlesex / England

New bornane derivatives, processes for their preparation and

their use

The invention relates to new bornane derivatives, processes for their preparation and in particular 10-bornanamine and 7,7-diraethylnorbornan-1-amines and their derivatives.

7,7-dimethylnorbornan-1-amine (i.e. 1-amino-7,7-dimethyl [2,2,1 bicycloheptane) is a well-known compound and has the formula

10-bornanamine (i.e. 1-aminomethyl-7,7-dimethyl [2,2,1] bicycloheptane) is also a known compound and has the formula

409839/1016

II

These two compounds have not yet become pharmaceutical Attributed to activities.

Antiviral activity of varying degrees has heretofore been noted in compounds that are in a wide variety of structures, in particular activity against rhinoviruses is not uncommon, activity against the most important: 'Influenza viruses are rare, however. When trying that The Applicant has carried out surprisingly good activity in the 10-bornanamine and 7,7-dimethylnorbornan-1-amine series against influenza viruses, in particular against H2N2 and H3N2 species, for example Iksha, Hong Kong 1/68 and England 42/72 strains were found.

It has, for example, a particularly meaningful anti-viral activity of this kind for 10-Borna amine and 7 _f 7-Dimethylnorbornan-amine 1-and their derivatives having a basic nitrogen atom gefunden.Die .The compounds of this series also because of their activity on the central nervous system, zBwegen their at-

algesic activity, important.

The invention relates to pharmaceutical agents which contain a pharmaceutical carrier or a diluent and a 7f7-dimethyl [2,2,1jbicycloheptane, which is in the 1-position contains a group R, in which R is an amino or aminomethyl group, or a derivative thereof which is a basic Containing nitrogen atom, and / or containing a physiologically acceptable salt thereof, the derivative being a compound where R is on the amino nitrogen and / or on the 10 carbon atom is substituted by one or more aliphatic, cycloaliphatic, araliphatic or aryl groups or, in the case

409839/1016

the amino group, is substituted by a heterocyclic group in which the nitrogen atom of the amino group is part of a heterocyclic ring, or, in the case of an N-substituted aminomethyl group, through an oxo group is substituted on the 10-carbon atom. The compounds just described in which R is substituted are themselves new compounds and are the subject of the present Invention.

The amino group can, for example, be mono- or disubstituted Be a group, the substituents generally containing up to a total of 12 carbon atoms on the nitrogen atom can.

Such aliphatic groups can be branched or straight-chain, saturated or unsaturated and substituted or unsubstituted be. They preferably contain 1 to 6 carbon atoms and can be, for example, alkyl groups (e.g. methyl, Ethyl, n-propyl and n-butyl), alkenyl groups (for example Allyl) or alkynyl groups (e.g. propargyl). The aliphatic group can be attached to the nitrogen atom of the amino group be bound by a double bond as in the case of an alkylidene group such as propylidene.

These aliphatic groups and in particular the alkyl groups can be substituted, for example, by amino, mono- or dialkylamino, imino (for example as in amidino), hydroxy, etherified or esterified hydroxy (for example Alkyloxy or alkanoyloxy), thiol or esterified or etherified thiol (for example alkylthio) groups.

When a basic substituent such as an amino group is present on the N-aliphatic substituent, an oxo group may be used in the α-position, based on the nitrogen atom of the R group, be present, with one base substituted Acylamino group, for example an aminoacetamido group, is formed. When R is a substituted aminomethyl group means, the oxo group can be in any α-position, based

409839/1018

_4- 2410A92

on the nitrogen atom.

Cycloaliphatic substituents can be, for example, cycloalkyl groups with 3 to 8 or more (e.g. up to 10) carbon atoms such as cyclohexyl and 7,7-dimethylnorbornan-1-yl.

Araliphatic substituents can, for example, be monocyclic Aralkyl, aralkenyl or aralkynyl groups such as benzyl, styryl and phenylethinyl groups. The araliphatic Group can be attached to the nitrogen atom of the amino group through a double bond such as in one Benzylidene group. The aliphatic parts of such araliphatic Groups preferably contain 1 to 6 carbon atoms.

Aryl substituents can, for example, be monocyclic Aryl groups such as phenyl or heterocyclic aryl groups which contain, for example, 5 or 6 ring members and which contain a or more heteroatoms, for example N, O or S, contain.

Substituted amino groups in which the amino nitrogen atom forms part of a heterocyclic ring can, for example, be saturated or unsaturated and contain 4 to 8, preferably 5 or 6, ring members, and they can contain a further, for example a second, heteroatom such as N, 0 or S. Examples of such groups are piperidino, morpholino, thiomorpholino, pyrrolidino, azetidino and piperazino groups. The heterocyclic ring may su ¹ itself - pi-.rtuiort isyin, for example by hydroxy or alkyl groups such as a methyl group as in a 4-MethylpiperazJno-Grvppe or by a hydroxy group as in a 3-Hydr ': -;. Sjazetidinogruppe. The heterocyclic ring may also be fused to a second ring rii _s, for example, a benzene ring, such as in a Isoindolinogruppe.

The heterocyclic ring can ebe.-if.alls by a Cycl -.;?}. yl ~: Vl. '' ohcii described be substituted, beiirpicj? jwei- ° -e

4 0 9 8 3 9 / ' } Β

in 1,3 _f 5-tris- (bornan-10-yl) -hexahydro-1,3,5-triazine.

The amino group in the group R of the invention

1 2

Compounds is present, can have the formula -NR R,

12th
wherein R and R, which can be the same or different, denote hydrogen atoms or aliphatic ^, cycloaliphatic, araliphatic or aryl groups as described above

1 2
or in which R and R together with the intermediate nitrogen atom form a heterocyclic ring as described above

1 2

ben form, or wherein R and R together form a divalent

mean aliphatic or araliphatic group.

When R is an aminomethyl group, one or both of the methyl hydrogen atoms on the 10 carbon atom can be be replaced by a substituent, which can be, for example, an aliphatic, cycloaliphatic, araliphatic or aryl (especially phenyl) substituent as generally described above. It can in particular one or two CL _g-alkyl substituents such as methyl or Ethyl groups may be present. When the 1O carbon atom is substituted, the amino group will usually, but not necessarily, be unsubstituted.

Acid addition salts and in particular physiologically acceptable acid addition salts are also a subject of the invention. Examples of such salts are the hydrochlorides, hydrobromides, phosphates, sulfates, p-toluenesulfonates, methanesulfonates, citrates, Tartrates, acetates, ascorbates, lactates, maleates and succinates.

Compounds which are particularly preferred for use in the present invention are those wherein R an amino, mono- or dialkylamino, aminomethyl, mono- or dialkylaminomethyl, mono- or dialkenylaminomethyl or 1-aminoethyl group or a group (especially a ine Aminomethyl group) means in which the nitrogen atom is part of a saturated 5- or 6-membered heterocyclic ring which forms a second heteroatom or one or more

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May contain substituents or the one with a second (for example a benzene) ring may be condensed. Most preferably the alkyl groups contain 1 to 4 carbon atoms and in particular, methyl or ethyl groups are preferred.

Specific compounds which are particularly preferred for their activity are those in which R is an aminomethyl group or the monomethyl, monoethyl, dimethyl, diethyl, monoailyl, Mono-n-butylamino-substituted derivatives thereof or a 4-methylpiperazinomethyl, piperidinomethyl, isoindolinomethyl or morpholinomethyl group or the amino-substituted derivatives, a 1-aminoethyl group or an amino, methylamino, Means ethylamino or dimethylamino group.

In tissue culture experiments carried out show compounds in which R is aminomethyl, mono- or dimethylaminomethyl, mono- or Diethylaminomethyl, mono-n-butylaminomethyl, N-methylpiperazinomethyl, Piperidinomethyl, morpholinomethyl, 'isoindolinomethyl, 1-Aminoethyl, amino or monomethylamino means high activity against the Iksha strain of Influenza Hy ^ virus.

The compounds in which R is aminomethyl, mono- and diethylaminomethyl-, mono-n-butylaminomethyl, N-methylpiperazinomethyl, allylaminomethyl, 1-aminoethyl, amino, mono- or dimethylamino or ethylamino, show a high activity against the England 42 / 72- Influenza H ₂ N ₂ virus strain.

Experiments carried out on mice show that certain Compounds give protection against Influenza England 42/72 H3N2 virus when administered orally. These connections are particularly preferred and are those in which R is an aminomethyl group or those substituted by methyl, ethyl or dimethylamino Derivatives thereof, a 1-aminoethyl, dimethylamino or morpholinomethyl group. It continued to be found that the diethylaminomethyl, 4-methylpiperazinomethyl and isoindolinomethyl compounds provide protection when administered intraperitoneally to mice.

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The physiologically active compounds according to the invention can, if desired, for administration together with a or more pharmaceutical (including veterinary) excipients or diluents or others medicinal agents are formulated, for example, for oral, topical, rectal or parenteral administration are suitable.

They can be used together with other medicines, for example with anti-inflammatory agents such as with steroids, for example ß-methasone-21-phosphate, or used with antibiotics such as tetracycline. The funds are expediently in Unit dose form before and each unit dose should generally be above 0.025, for example 0.05 to 4 g and preferred 0.1 to 1.0 g of active compound at 1 to 5 times more common daily administration or for intranasal or inhalation administration, for example 6 to 8 times daily, This total daily dose should generally be above 0.05 g and, for example, from 0.10 to 7 g. The carrier or drug diluent will generally be a solid carrier or diluent, a sterile liquid or a liquid containing one or more stabilizers, flavoring agents, suspending agents, Use sweeteners, emulsifiers or preservatives.

When the agent is in aerosol form, each spray should be approximately 1 / 20-1 / 40 of that given above The total daily dose is usually 1/8 of the dose amounts given above. The doses given above are those for adults (body weight about 70 kg) and they can of course be varied for children or animals according to body weight.

Solid preparations for oral consumption are usually provided in unit dosage form and include, for example,

-4 09839/101 B

wise tablets, capsules, lozenges, chewing gum, liquids that contain the drug. Known carrier for such preparations can be sugars, starches, sugar alcohols, gelatin, chicle gum, cocoa butter, etc. together with other processing agents acting as binders, lubricants, stabilizers, coatings, flavorings and colorants required are. The means can also be in the form of liquid oral preparations for ingestion such as of solutions, suspensions, syrups, elixirs, emulsions, granules for reconstitution before use, which can also contain suspending agents, emulsifying agents, stabilizing agents and preservatives, and they can likewise contain acceptable sweeteners, flavoring agents, or coloring agents. The connections can be based on local application The mucous membranes of the nose and throat or pharynx are formulated and they can be in the form of more liquid Sprays, aerosols or powder inhalants, as nasal drops or ointments, as throat spreads, gargles or be formulated in the form of similar preparations. Topical formulations for treatment of the eyes can be used in oily or aqueous media in the form of known eye preparations and eye lotions, for example as creams, ointments, Eye drops and lotions can be formulated. Suppositories can contain common ingredients, for example theobroma oil, Polyglycols, optionally together with surface-active agents, contain. The injectable preparations can be used in In the form of aqueous oily solutions, emulsions, suspensions or solids for reconstitution before use. Suitable carriers include, for example, sterile, pyrogen-free water, parenterally acceptable oils, oily esters or other non-aqueous media such as propylene glycol, which are desired enf alls suspension, dispersion, stabilization, May contain preservatives, solubilizers, emulsifiers or buffering agents.

Particularly suitable forms for administration are tablets, solutions for injection, nasal sprays or drops, sprays

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for the respiratory tract, e.g. aerosols for inhalation.

The compounds according to the invention which contain a methylene group in the α-position, added to the nitrogen atom of the R group, can be obtained by reducing the corresponding amide
getting produced.

This reaction can be carried out, for example, with a hydride reagent
which is able to reduce amides to amines such as lithium aluminum hydrod or diborane, in
an inert organic solvent, for example a hydrocarbon solvent such as benzene or toluene or
in an ether solvent such as diethyl ether or tetrahydrofuran. The reaction with lithium aluminum hydride is suitably carried out at the reflux temperature of the reaction mixture, although lower temperatures can be used if desired. The reaction with diborane, for example, at temperatures of -10 to +30 ⁰ C, suitably at room temperature, are performed. The amine formed is expediently isolated in the form of a salt, for example the hydrochloride.

For example, amino compounds containing an araliphatic substituent or an aliphatic substituent can be prepared by reducing the correspondingly substituted amide compound (ie a compound
where R is an acylamino or acylaminomethyl group).

The amides required as starting materials for the latter reaction are readily obtained by acylation of the parent amino compound, for example with an acid halide corresponding to the desired substituent. This reaction is suitably carried out in the presence of an agent
carried out to bind the acid, and suitable basic conditions can be selected by using an excess of the starting amino compound and preferably in an

4 09839/1016

Being of an added base is working.

Compounds according to the invention in which R is a substituted aminomethyl group (for example compounds with a 1-substituent of the formula -CHpNR R), can expediently by reducing the corresponding 7 »7-dimethylnorbornane-1-carbonamides getting produced.

The 1-carboxamides, the _t as starting materials in the preparation of aminomethyl

are used are new and are the subject of the present invention. The invention thus relates to N-substituted ones 7,7-dimethyl-norbornane-i-carbonamides. The N-substituents can of course be the same as those described with reference to the amino-substituted 1O-Bornanamines became.

As indicated above, certain of these amides are antiviral Activity similar to that of the amines in addition to being used as intermediates in the preparation of the invention 1O-Bornanamine can be used. These are amides, in which the N-substituent itself is a basic substituent, for example, an aliphatic substituent such as an alkyl group substituted by an amino group is, contains. An example of such a compound is a compound in which R is 4-methylpiperazinocarbonyl group means.

The 1-carbonamides can, for example, by reacting 7,7-dimethyl-norbornane-1-carboxylic acid or preferably one reactive derivative thereof such as a halide (e.g. 7,7-dimethyl-norbornane-i-carbonyl chloride) with a primary or secondary amine corresponding to the mono- or disubstituted amino group desired in the amide.

This reaction is preferably carried out at low temperature, for example at -80 to 10 ⁰ C, in the presence of an agent

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to bind the acid, (for example a base) carried out. These basic conditions can also occur Using an excess of the amine can be obtained. The reaction is suitably carried out in a non-polar, organic solvents such as in an ethereal solvent, for example diethyl ether, carried out.

The T ^ -dimethyl-norbornane-i-carbonyl chloride, which is preferred Used in the latter reaction is a known compound and is readily prepared from 7,7-dimethyl-norbornane-i-carboxylic acid manufactured.

Compounds according to the invention which contain a monomethylamine © substituent can, for example, by reduction an ester of the corresponding carboxyamino compound can be prepared. This ester is suitably an alkoxycarbonylamino compound.

The reduction is desirably carried out with a hydride reducing agent, preferably lithium aluminum hydride, carried out in, for example, an ether solvent such as diethyl ether. The reaction is preferably carried out at the reflux temperature of the medium. The amine formed becomes useful isolated as a salt by adding an acid, e.g. hydrochloric acid.

Methylamino compounds can also be obtained by methylation (for example reductive methylation with formaldehyde in Presence of formic acid or sodium borohydride) of the basic amine.

Compounds according to the invention, wherein the nitrogen atom of the amino group by a double bond with an aliphatic or araliphatic substituents can be produced by mixing the unsubstituted amino compound (which may be in the form of a salt) with an aldehyde

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or ketone (for example acetone or benzaldehyde) in a suitable medium, preferably with azeotropic removal of water, for example using toluene or benzene or a chlorinated hydrocarbon as solvent. When formaldehyde is used in this reaction, the aforementioned triazine is obtained.

Compounds in which R is an aminomethyl group in which one of the hydrogen atoms on the methyl carbon atom is replaced by a substituent and in which the amino group is unsubstituted, by reducing the corresponding 10-Hydroxyimino- (ketoxime) -bornans can be produced. This reduction can be carried out, for example, by hydrogenation a nickel catalyst or by reduction with zinc and acetic acid, lithium aluminum hydride or sodium in the presence of a lower alkanol such as ethanol.

The 10-hydroxyimino compound used as a starting material in of the above reaction is required, by condensation of the corresponding ketone (i.e. a compound of Formula II above, which contains the group -COR "^ in the 1 position, wherein R is the desired 10-substituent) with Hydroxylamine can be obtained. This reaction is conveniently carried out in an aqueous medium, preferably at reflux temperature of the medium. The hydroxylamine is usually used in the form of a salt, for example the sulfate or hydrochloride, in the presence of a base.

The ketones that are required for the latter reaction can be obtained, for example, from 7,7-dimethyl-norbornane-i-carboxylic acid by reaction with a metal (e.g. lithium) derivative of the formula MR, where M is the metal and R is the desired hydrocarbon substituent in the 10-position.

The amino compounds with an aryl substituent can be

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for example by treating the basic amino compound ("for example in the form of a salt, for example a lithium salt) with a benzyne. That for Benzyne required for this reaction can suitably be obtained by reaction of an aryl halide (e.g. chloride or bromide) with an excess of the lithium salt of the corresponding Basic amino compound are produced.

Compounds in which the amino group is substituted by an aliphatic, cycloaliphatic or araliphatic group is can also by reacting the basic amine with a compound of the formula RX, wherein R is the desired substituent and X represents an easily eliminable group such as a halogen atom such as a chlorine atom or a toluenesulfonyl group getting produced. This reaction can be carried out in a polar solvent (such as dimethylformamide) or in acetone carried out in the presence of a base, for example sodium hydride, preferably using an excess of amine will. The implementation is particularly suitable in the preparation of disubstituted amines, it can also be used for Preparation of monosubstituted compounds can be used. Alternatively, the use of an epoxy results in this Reaction a process for the production of hydroxyalkylamino compounds.

Compounds in which the amino nitrogen atom is a member of a heterocyclic ring can be obtained by cyclizing those hydroxyalkylamino compounds which form a group capable of to be eliminated, contained, produced. Such a product can, for example, by reacting the amine be made with epichlorohydrin. The cyclization can be carried out, for example, by changing the starting materials heated in solution.

Compounds - in which R is an aminomethyl group and that 1O-carbon atom is substituted, can by reduction the corresponding nitromethyl compound can be prepared.

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The reduction can be carried out, for example, with a hydride reducing agent (such as lithium aluminum hydride or diborane). The reaction is generally used for the production of

5 6 5

Suitable bonds, in which R-CR ^ R NH ₂ , in which.R has the meaning given above and R is a hydrogen atom or an aliphatic, cycloaliphatic or araliphatic group. It is preferred that R is a lower alkyl, for example, a methyl group and R is a hydrogen atom od.eine lower alkyl, zBMethylgruppe, bedeuten.Am most preferably R ⁵ and R ° are both methyl groups. The nitro derivatives required for the latter reaction can be prepared by reacting a compound of the formula R ^ X with a corresponding nitro compound in which the carbon atom of the group R is unsubstituted or monosubstituted; (ie a compound where R

fi 6

-CHR NO ₂ means in which R has the meaning given above.) The reaction conditions are generally similar

5
as described above for the reaction of RX with an amine and it is desirable to work anhydrous. A strong base such as an alkali metal hydride is advantageously added to form the reacting species which is a nitronic acid anion.

The monosubstituted or unsubstituted nitro compounds can themselves by oxidation of a corresponding amine or ketoxime (i.e. a compound in which R -CHR NHp or -CR = N0H means). The oxidation can, for example, with a peracid (for example m-chloroperbenzoic acid or pertrifluoroacetic acid) in a hydrocarbon or chlorinated hydrocarbon solvent is preferred be carried out at room temperature. Making more suitable. Ketoxime is described above.

Compounds wherein the nitrogen atom of the group R is substituted by a Aminoacryl- or mono- or Dialkylaminoacylgruppe may be prepared by reacting the corresponding HaIogenacyl- _r (for example Bromacyl-) compound with ammonia or

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2A10492

or mono- or dialkylamine can be obtained. A suitable solvent for this reaction is an alcohol, for example Methanol. An excess of ammonia is preferred.

Compounds in which the nitrogen atom of R is replaced by a haloacyl group is substituted in which the halogen atom is separated from the carbonyl group by at least 2 carbon atoms, can be cyclized to give a corresponding lactam. The cyclic amide group can then. be reduced, whereby a basic compound according to the invention is obtained. The cyclization can take place under basic conditions, i.e. under Use sodium hydride in a polar aprotic solvent such as dimethyl sulfoxide. The reduction of cyclic amide group can be made, for example, using a hydride reducing agent such as lithium aluminum hydride or diborane be performed. ,

Compounds in which the amino nitrogen atom is a member of a heterocyclic ring can also be prepared by reacting the basic amine with a compound which contains two easily eliminable groups as mentioned above. the

the latter compound can, for example, be the 'formula XR ¹ X

7 sit, where X has the definition given above and R ' means a divalent alkylene group (which may be interrupted by an oxygen or sulfur atom) or a cyclic group containing two monovalent alkylene groups (for example, an o-xylenyl group). The implementation can for example as above for the reaction of R ^ X with an amine be performed.

Compounds which contain an amino group substituted on an aliphatic or araliphatic group can likewise by reduction of the corresponding compound in which the amino nitrogen atom on the substituent is via a ^ double bond is bound to be produced. The reduction can be carried out, for example, with a metal hydride, for example as above described, be carried out.

4 0 9 8 3 9/1016

-16- 2410A92

The following examples illustrate the invention without restricting it. Temperatures are given in ^0C.

Examples 1 to 8

Production of T ^ -dimethyl-norbornane-i-carbonamides

The eight amides, the properties of which are summarized in Table I below, are made according to the following general Process made. Changes to the procedure are listed in the footnote of the table.

A solution of freshly made 7,7-dimethyl-norbornane-icarbonyl-chloride (10 mmol) in dry ether (usually about 10 ml) is cooled in an ice bath and stirred, while the appropriate amine (2 equiv) is added dropwise over 5 to 10 minutes. After the addition is complete can warm the mixture to room temperature. After 1 to 2 hours, the reaction mixture is between chloroform and dilute hydrochloric acid and the organic extract is washed with dilute sodium carbonate and water and then dried over magnesium sulfate. Evaporation of the organic solvent gives the crude amide, which is purified by sublimation at about 0.1 mm and / or by crystallization.

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Table I 7,7-Dimethyl-norbornane-i-carbonamides

Amide IvI (Kofier) Empirical
formula ι
found
the C. found
the H 1 found
the berecfc
net ro example
No. X C ₁₁ H ₁₉ NO 72.85 calc
net 10.8 calc
net 7.5 7.75 0
5.9X-
LD 1 NHM ₆ Cl) ₁₁₆ . ₁₁₇ (2) C ₁₂ H ₂₁ NO 73.4 72.9 10.5 10.55 7.1 7.2 11.2 2 NHEt 113-114.5 ^ C ₁₄ H ₂₅ NO 73.8 10.8 3 NHBu 72.5-73.5 C ₁₂ H ₂₁ NO j 73.4 10.6 6.9 7.2 4th (4) "(5)
_{NMe 2} ^v '91-92 ^W ' C ₁₄ H ₂₅ NO 75.0 73.8 11.2 10.8 6.05 6.3 5 · NEt ₂ 38-40 ^ C ₁₅ H ₂₅ NO 75.3 11.3 6th ■ O C ₁₄ H ₂₃ NO ₂ 70.5 9.85 5.75 7th Qd 117-118 C ₁₅ H ₂₆ N ₂ O 71.6 70.9 10.2 9.8 11.2 8th NNMe 113-114 71.9 10.5

Footnotes to Table I.

(1) The acid chloride (25 mmol) in ether (25 ml) is at -70 ° stirred while a large excess (10 ml) of liquid methylamine is added.

(2) After crystallization from ether.

(3) The crude amine is chromatographed on silica before sublimation and crystallization from petroleum ether cleaned.

(4) The reaction mixture is left to stand at room temperature for 1 week.

(5) After crystallization from petroleum ether.

(6) The crude amine is chromatographed on silica cleaned before sublimation.

(7) The reaction mixture is diluted between chloroform and Split hydrochloric acid and add sodium carbonate to the aqueous layer until basic and extracted with chloroform. Evaporation of the organic solvent gives a solid, which by sublimation is cleaned.

Examples 9 to 16

Eight 10-Bornanamines are made according to the following general Process made. Their properties are listed in Table II. Changes to the procedure are in the Given in footnote to Table II.

A solution of the appropriate amide in the chosen solvent (See Table II) is carefully made into a suspension of an excess of lithium aluminum hydride in the same solvent given and the resulting mixture is refluxed until the reaction, which can be seen by thin layer chromatography pursued, ended. Excess lithium aluminum hydride is destroyed by careful addition of water, further Benzene (or other ether or chloroform) is added and the insoluble inorganic material is through Filtration removed. The organic layer is washed with water, dried (MgSO ^) and evaporated in vacuo. That

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the remaining crude amine is dissolved in ether, about 8N more in ethanol Hydrogen chloride is added and then the precipitated amine hydrochloride is separated off by filtration and dried.

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Amir '

10 NHEt

16

Reduction solvents

E.g. R
No.

9 NHMe tetrahydrofuran

Benzene.

. (D

11 NHBu tetrahydrofuran

12 NMe ₉ tetrahydrofuran

13 NEt ₂ 'benzene

1 '+' Ny tetrahydrofuran

15, \ _ß tetrahydrofuran

BenzPl

Table II 1Q-Bornanamine hydrochloride

Empirical
Formula

found

^C 14 ^H 28 ^C1N

64.3

66.5

68.05

68.25

69.4

64.6

.2H ₂ O 51.7

calc

ige * .;

64.85

66.2

68.4

68.4

69.85

64.7

52.] s \). P

? erech

10.5

11.3

11.55

11.55

10.15

10.9 11.1 11.5

11.5 10.95 10.1 9.9

Cl

17.3 15.4 14.4

14.4

13.75

13.7

calc

17.4 16.3 14.4

14.4

13.75

13.65

.f. tae-

6.9 6.0 5.55

5.55

5.2

5.45

8.0

reck.

6.9 ^ O

6.4 ^ω . ro

5.7

5.7

5.4:

5.4

8.1

It

I O) • Η Ή O ft CQIO

OJ

IA

σν in c- in <l σ \ co in co co <t co in <i-

(N (M CM CvJ CvJ (M CvI

VO

t in

CvI I

CvI

σ \ ο

cm <j in vo

409839/1 0 1.6

Footnotes to Table II

(1) After the destruction of excess hydride and after the removal of the inorganic material, the Benzene solution extracted with dilute hydrochloric acid. The acidic solution is added until a basic reaction occurs and extracted with chloroform, the crude amine being obtained as an oil, which is converted into its hydrochloride.

(2) Change in crystalline shape about 170 °.

(3) After destroying the excess hydride and removing the inorganic material, the reaction mixture becomes divided between chloroform and dilute hydrochloric acid. The acidic solution is made basic and extracted with chloroform to obtain the crude amine, which is converted into its hydrochloride.

(4) Change in crystalline form at about

(5) After crystallization from chloroform.

(6) The crude amine is determined by preparative thin layer chromatography Purified over silica, converted into the dihydrochloride and crystallized from ethanol.

Example 17

1- (1'-Aminoethyl) -7.7-dimethyl-norbornane hydrochloride (i) 7f7-Dimethylnorbomyl-1-methyl-ketone oxime

A solution of 7,7-dimethylnorbornane-1-carboxylic acid (2.54 g) in ether (60 ml) is added dropwise under nitrogen with a Treated 2 M solution of methyllithium in ether (24 ml). After the addition is complete, the mixture is refluxed for 2.5 hours warmed up. The cooled mixture is washed with 2N hydrochloric acid, sodium carbonate solution and water and then over Dried sodium sulfate. Evaporation of the ether gives 7,7-dimethylnorbornyl-1-methyl ketone as a pale yellow oil (2.49 g);

max ( ^{in CHBr} 3 ^ ^{1682 cm -1} x This oil (2.42 g) in ethanol (60 ml) is treated with hydroxylamine hydrochloride (1.29 g) and N-sodium hydroxide solution (63 ml) and the mixture is Left overnight at room temperature and then 0.5 hours

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heated to reflux. The cooled reaction mixture is extracted with chloroform, the extracts are washed with water and dried (Na ^ SOi) and the solvent is im Removed vacuum to obtain the crude, crystalline product (2.65 g ^ which is recrystallized from aqueous ethanol, whereby the title compound is obtained, melting point 109 ° to 111 ° (Kofier).

A similar sample, m.p. 109.5 to 110.5 ° (Kofier) showed the following analysis:

calculated: C 72.9% H 10.55% N 7.75% found: 73.05 10.7 7.4

(ii) 1- (1'-Aminoethyl) -7,7-dimethyl-norbornane hydrochloride

A solution of 7,7-dimethyl-norbornyl-1-methylketone oxime (253 mg) in ethanol (20 ml) containing Raney nickel catalyst is shaken with hydrogen for 22 hours. The catalyst is removed by filtration and the solution is evaporated in vacuo to give an oil which is partitioned between chloroform and water. The chloroform layer is extracted with 2N hydrochloric acid (50 ml), added with sodium carbonate solution until basic, and extracted with chloroform. The organic extract is washed with water, dried (MgSO ^ ₊ ) and evaporated to give a yellow oil. This oil is dissolved in ether, ethanolic hydrogen chloride is added and the precipitate is separated off by filtration to give the title compound which sublimes at about 263 ° (Kofier).

Example 18

1-methylamino-7,7-dimethyl-norbornane hydrochloride

A solution of 1- (methoxycarbonylamino) -7,7-dimethyl-norbomane (197 mg) in ether (5 ml) is added to a suspension of lithium aluminum hydride (80 mg) in ether (5 n4) and the resulting The mixture is refluxed for 3 hours. Above-

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Excess lithium aluminum hydride is decomposed by adding water and the precipitated inorganic material is removed by filtration. The ether solution is washed with water, dried (MgSO ^) and the solvent is evaporated. Treatment of the remaining oil in ether with 8N ethanolic hydrogen chloride gives i-methyl-amino ^^ - dimethylnorbornane hydrochloride, sublimation point 260 ° (Kofier) analysis: C ₁₀ H ₂₀ ClN

calculated: C 63.3% H 10.65% Cl 18.7% N 7.4% found: 63.1 10.4 18.7 7.4

Example 19
1-ethylamino-7 ', 7-dimethyl-norbornane hydrochloride

A solution of 1-amino-7,7-dimethyl-norbornane (1.022 g) in pyridine (10 ml) is cooled in an ice bath and while being Acetyl chloride (1 ml) is added dropwise and stirred. The ice bath is removed and the mixture is kept at room temperature until left to finish the reaction. Dilution with water, acidification with dilute hydrochloric acid and Extraction with ether gives the crude product, which is purified by filtration through a small column of neutral aluminum oxide and which is crystallized from ether-petroleum ether, 1-acetamido-7,7-dimethyl-norbornane, melting point 133 bis 134 ° (Kofier), obtained after previous softening.

The above N-acetyl compound (776 mg) in dry ether (25 ml) is added to a mixture of aluminum aluminum hydride (1 g) in ether (75 ml) and the mixture is refluxed Heated for 2 hours. Excess reagent is destroyed by adding water (5 ml) and the precipitated material is removed by filtration. Extraction of the filtrate with ether gives the crude ethylamino compound, which is dissolved in ether and treated with ethanolic hydrogen chloride. The insoluble amine hydrochloride is separated off by filtration and crystallized from ethanol-ether to give the title compound; sublimates over 150 °.

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Analysis: C ₁₁ H ₂₂ ClN calcd: C 64.85% H 10.9% N 6.85% Cl 17.4% found 65.0 11.0 6.95 17.4

Example 20

1O-allylamino-bornan hydrobromide and 10-diallylamino-bornan hydrochloride

A mixture of 1Q-Bornanamine (1 g), sodium hydride (0.16 g) and dimethylformamide is stirred for 15 minutes. It is then cooled in an ice bath and allyl bromide (0.55 ml) is added. The mixture is stirred for 2 hours at room temperature and then partitioned between ether and water. The organic layer is dried (MgSO.) and evaporated. The residue is prepared using thin layer chromatography a mixture of 5% methanol in chloroform to develop the plates. The more polar faction (0.6 g) is dissolved in dry ether and treated with hydrogen chloride, 10-allylamino-bornane hydrobromide (0.65 g) is obtained.

The less polar fraction (0.34 g) is dissolved in dry ether and treated with hydrogen chloride, 10-diallylamino-bornane hydrochloride (0.25 g), m.p. 163-164 °.

^C 16 ^H 28 ^{C1N '1/4 H} 2 ° Calculated: C 70.0% H 10.65% Cl 12.9% N 5.1% Found: 70.3 5.2 10.7 13.2

Example 21

(i) 10-bromoacetamido-bornane

10-Bornanamine (0.5 g) in dry ether (30 ml), the pyridine (0.45 ml) is mixed with a solution of bromoacetyl bromide (0.3 ml) in ether (5 ml) for 1 minute at -80 ° Stirring treated. The mixture is allowed to warm to room temperature and after another 30 minutes it becomes between ether and water shared. The organic layer is washed with 2N hydrogen chloride Acid solution and then washed with water. she will

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dried (MgSO.) and evaporated. The residue (0.73 g) is purified by preparative thin-layer chromatography and by crystallization from petroleum ether (boiling point 60 to 80 °), whereby the title compound is obtained (0.48 g), melting point 89 °. C ₁₂ H ₂₀ BrNO

calculated: C 52.55% H 7.35% Br 29.1% N 5.1% found: 52.4 7.3 28.9 5.0

(ii) 1O-aminoacetamido-bornan hydrochloride

10-bromoacetamido-bornane (0.36 g) becomes a 15% solution from ammonia in methanol (10 ml) and stored at room temperature for 20 hours. The mixture is then evaporated and the residue is partitioned between 2N hydrogen chloride acid solution and ether. The aqueous layer becomes mixed with sodium hydroxide until a basic reaction and extracted into ether. The organic extract is made with water washed, dried (MgSO,) and evaporated. The residue (0.18 g) is dissolved in dry ether and. with hydrogen chloride treated to obtain the title compound (0.19 g), m.p. 233-235 °.

CI / 4 H ₂ O

Calculated: C 57.35% H 9.4% Cl 14.1% N 11.15% found: 57.5 9.2 13.6 11.2

Example 22

(i) 1-Bromoacetamido-7,7-dimethyl-norbornane

1-Amino-7,7-dimethyl-norbornane (1 g) in dry ether (50 ml) containing pyridine (1 ml) is mixed with a solution at -80 ° treated from bromoacetyl bromide (0.7 ml) in ether (10 ml). The mixture is then allowed to warm to room temperature and they is stirred for 1 hour. It is then divided between ether and 2 η hydrochloric acid solution. The organic layer is washed with water, dried (MgSO.) and evaporated. The residue (1.48 g) is extracted from petroleum ether (b.p. 60 to 80 °) crystallizes to give the title compound (1.35 g),

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M.p. 97 to 98 °.
C ₁₁ H ₁₈ BrNO

calculated: C 50.8% H 7.0% Br 30.7% N 5.4% found: 51.0 7.1 30.5 5.2

(ii) 1-Aminoacetamido-7 ^ -dimethyl-norbornane hydrochloride

1-Bromoacetylamino-7,7-dimethyl-norbornane (1.12 g) is added to a 15% solution of ammonia in methanol (50 ml) and stored at room temperature for 20 hours. The mixture is then evaporated and the residue is partitioned between ether and water. The organic layer is dried (MgSO ^) and evaporated. The residue (0.43 g) is dissolved in dry ether and treated with hydrogen chloride, whereby the title compound is obtained (0.44 g), melting point 179 ° to 182 °. C ₁₁ H ₂₁ ClN ₂ O-IA H ₂ O

Calculated: C 55.7% H 9.1% "Cl 14.9% N 11.8% found 55.8 9.1 15.1 11.9

Example 23
N-ethyl-10-bornanamine hydrochloride

A solution of boron trifluoride etherate (5.75 ml) in dry Tetrahydrofuran (5 ml) is added dropwise over 5 minutes to a stirred mixture of sodium borohydride (1.14 g) in dry tetrahydrofuran (18 ml) at -10 °. the The mixture is stirred at room temperature for 1 hour and then a solution of N-ethyl ^^ - dimethyl-norbornane-i-carbonamide (0.5 g) in dry tetrahydrofuran (5 ml) was added. After a further 20 ^ hours the mixture becomes ice-water (50 ml) was added. Concentrated hydrochloric acid (10 ml) is added and the mixture is refluxed for 30 minutes warmed up. It is then cooled and distributed between ether and dilute sodium hydroxide solution. The organic layer is washed with water, dried (MgSO ^) and evaporated. The residue is dissolved in dry ether and washed with hydrogen chloride treated, whereby the title compound (0.5 g)

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7 L 1 - '. 9 2 , sublimates over 285 °.

Example 24

1 - (1-amino-ethyl) -7., 7-dimethyl-norbornane hydrochloride

A boiling solution of 7,7-dimethylnorborn-i-yl-methylketone oxime (2.9 g) in absolute ethanol (100 ml) is treated with sodium (8 g). After all of the sodium reacts the mixture is cooled and divided between ether and water. The organic layer is dried (MgSO /) and evaporated. The residue (1.89 g) is dissolved in dry ether and treated with hydrogen chloride, whereby the Title compound (2.16 g) is obtained, sublimed over 260 °.

Example 25
N- (iO-Bornyl) -isoindoline hydrochloride

A solution of 10-bornanamine (1.274 g) in dimethylformamide (10 ml) containing triethylamine (2.31 ml) is cooled in ice and stirred while a solution of a, a'-dibromo-o-xylene (2.195 g) in dimethylformamide (5 ml) is added. The mixture is kept at room temperature for 24 hours and then diluted with water and several times with chloroform extracted. The combined organic extracts are washed well with water and dried (MgSO /) and evaporated in vacuo, an orange oil (3.16 g) is obtained. This oil in ethanol (15 ml) is mixed with a slight excess Treated with ethanolic hydrogen chloride, ether is added and the precipitated hydrochloride is separated off by filtration and recrystallized from ethanol-ether to give the title compound (1.4 g), m.p. over 300 ° after a change the crystalline form at about 260 °.

calculated: C 74.1% H 9.0% Cl 12.15% N 4.8% found: 74.4 9.1 12.2 4.65

OFUGmA INSPECTED

409839/101 6

2AK'A92

Example 26 10-Allylaminobornane hydrobromide

A solution of 10-bornanamine (prepared by adding to the basic reaction with sodium hydroxide of 1.517 g of 10-bornanamine hydrochloride) in acetone (20 ml), the allyl bromide (0.68 ml) becomes 3.5 at room temperature

Stored for days, during which time a small amount of solid crystallized. The solution is evaporated to approximately one third of its original volume, cooled to 0 ° and the crystalline material is collected by filtration to give the title compound, m.p. above 295 ° with slow decomposition.
C ₁₃ H ₂₄ BrN

Calculated: C 56.95% H 8.8% N 5.1% Found: 56.6 8.6 5.1

Example 2?

1,3,5-tris- (bornan-10-yl) -hexahydro-1,3,5-triazine

10-Bornanamine (824 mg) in benzene (10 ml) is treated with formaldehyde (37%, 0.44 ml) and the mixture is stirred at room temperature for 1 hour. Finely divided pellets of sodium hydroxide are added to the heterogeneous mixture, which is then separated from the aqueous layer. Evaporation of the solvent in vacuo gives a crystalline solid which is recrystallized from ether-methanol to give the title compound (490 mg), melting point 175 ° to 180 ° (sealed capsule).
C ₃₃ H ₅₇ N ₃

Calculated: C 79.9% H 11.6% N 8.45% Found: 79.7 11.4 8.25

Example 28,

1O-benzylamino-bornan hydrochloride

10-Bornanamine (824 mg) in toluene (20 ml) is mixed with benzaldehyde

409839/1016 orksinal inspected

(0.55 ml) treat 3-t and the solution is refluxed with a Dean and Stark water trap for 4 days. Evaporation of the solvent in vacuo gives impure 10-benzylidene-10-bornanamine, which is dissolved in dimethoxyethane (10 ml) containing lithium aluminum hydride (112 mg). The resulting mixture is refluxed for 2.25 hours, cooled and excess hydride is decomposed by adding water. The precipitated inorganic material is removed by filtration and the solvent is evaporated in vacuo. The remaining gum is triturated with 2N hydrochloric acid, insoluble hydrochloride being obtained, which is collected by filtration and then partitioned between ether and 2N sodium hydroxide. The dried ether layer is evaporated in vacuo, giving a yellow oil which is dissolved in ether and treated with ethanolic hydrogen chloride. The precipitated solid is collected and recrystallized from water, giving the title compound, melting point 310 °.
C ₁₇ H ₂₆ ClN

calculated: C 72.95% H 9.35% Cl 12.65% N 5.0% found: 72.65 9.65 13.3 4.95

Example 29

1-Dimethylamine-7,7-dimethylnorbornane hydrochloride

A mixture of 1-amino-7,7-dimethylnorbornane (71Qng), formic acid (98%, 1.4 ml) and formaldehyde (37%, 2.4 ml) are heated on a steam bath for 15.5 hours. The chilled solution is poured into 2N sodium hydroxide solution and extracted with ether. The washed extract is evaporated to give a mobile oil which is dissolved in ether and mixed with a small excess of ethanolic hydrogen chloride is treated. The precipitated hydrochloride is collected by filtration and crystallized from ethanol-ether to give the title compound (627 mg), sublimed over 150 °, m.p. 208 up to 209 °.

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calculated: C 64.85% H 10.9% Cl 17.4% N 6.7% found: 64.75 10.85 17.5 6.7

Example 30

7,7-dimethyl-1-morpholino-norbornane hydrochloride

A stirred mixture of 1-amino-7,7-dimethyl-norbornane (0.7.g), potassium carbonate (0.77 g) and 2,2'-dichlorodiethyl ether (3 ml) is heated at 130 ° for 2 hours. The reaction mixture is then cooled and between ether and 2N hydrogen chloride acid distributed. The aqueous layer is separated, made basic and extracted into ether. The organic layer is dried and evaporated. The residue (0.8 g) after purification by chromatography is in .trockenem ether dissolved and treated with hydrogen chloride to give the title compound (0.33 g), m.p. 243-246 °.

Example A table

7,7-dimethylnorbornane-i-amine hydrochloride. 250 mg

Lactose 30 mg

Gum arabic 15 mg

Magnesium stearate 5 mg

Sufficient water is added to the active ingredient to form a granulating liquid and then the pH is adjusted adjusted to about 5.0 using citric acid. The gum arabic is dissolved and this solution is used to granulate the lactose. The ingredients are then passed through a sieve with a mesh size of approx. 0.8 mm (20 mesh) (B.S.), dried, lubricated with magnesium stearate and pressed.

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Example B. injection

Antiviral Compound 1.0% w / v

Sodium chloride 0.80%

Water for injection to 100%

The sodium chloride and the antiviral compound are dissolved in water for injection. Water gets up to volume of 100% is added and then the solution is mixed. she will filtered and filled into ampoules, which are then sealed and sterilized in an autoclave.

Similar preparations containing 2.0% w / v can be found. Antivirus connection contain, manufacture.

Example C eye drop

Antiviral Compound 2.0% w / v

Propylene glycol 5.0%

Sodium chloride 0.6%

Uodium edetate ... ...., L. λ. 0.01%

Thimerosal 0.01%

Methyl p-hydroxy benzoate 0.03%

Propyl p-hydroxy benzoate 0.02%

Butyl p-hydroxy benzoate 0.01%

distilled water to 100%.

The p-hydroxy-benzoates are dissolved in the propylene glycol and the solution is poured into water and then mixed. The thimerosal, sodium chloride and the antiviral compound are added and dissolved. Then you fill up to 100% up and mixed. The solution is sterilized by filtration and aseptically filled into polyethylene eye drop bottles, which have previously been sterilized with γ rays.

409839/1 016

Example D Drain Nas

antiviral compound 2.0% w / v

Chlorobutol 0.5%

Sodium chloride. 0.7%

distilled water to 100%

The chlorobutol is dissolved in water, the solution is ^{heated to 60 °} C., cooled and then the sodium chloride and the antiviral compound are added. It is made up to the final volume, clarified by filtration and filled into suitable glass bottles equipped with a dropper.

Example E. Nasal aerosol

Example (i) (for doses of 1000 / Ug)

antiviral compound 1.17% w / w

Ethanol 30%

Dichlorodifluoromethane 35%

Dichlorotetrafluoroethane to 100%

The antiviral compound is dissolved in ethanol. The required Amount of this solution is filled into aluminum aerosol bottles or plastic-coated glass aerosol bottles, sealed with a measuring valve delivering 85 mg / spray and pressurized by passing through the valve introduces the required amount of the required mixture of dichlorodifluoromethane and dichlorotetrafluoroethane.

Example (ii) (for doses of 1 mg)

antiviral compound 1.17% w / w

Sorbitan trioleate 0.59% w / w.

Dichlorodifluoromethane 50.0%

Trichlorofluoromethane to 100%

The antiviral compound is micronized. The sorbitan trioleate is mixed with the trichlorofluoromethane (which ^{is cooled to +10 0} C) and then becomes the antiviral compound

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dispersed in this mixture. The required amount of this mixture is poured into containers (as above) with a measuring valve (as above) and filled with dichlorodifluomethane (as above) under Pressure put.

Example F Inhalation aerosol

Example (i) (doses of 1 mg)

antiviral compound 1.17% w / w

Dichlorodifluoromethane 70%

100% ethanol

procedure

Either procedure A or procedure B can be carried out.

A. The antiviral compound is dissolved in the alcohol, the solution (cooled to -50 ⁰ C) to dichlorodifluoromethane added, the reaction mixture is sealed described mixed and in aerosol bottles or filled -büchsen and with valves as described above for the nasal aerosols.

B. The antiviral compound is dissolved in the alcohol. The required amount is in bottles or cans like Filled as described above and provided with suitable measuring valves as described above. The mixture will be as above described with the required amount of dichlorodifluoromethane under pressure.

Example (ii) (doses of 1 mg)

antiviral compound 1.17% w / w

Sorbitan trioleate 0.59%

Dichlorodifluoromethane 70.0%

Trichlorofluoromethane - to 100%

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Procedure as in Example E (ii).

Example G suppositories

antiviral compound. 200 mg

Suppository base to 2.0 g

(This can be made from a wide variety of branded natural and semi-synthetic medical stocks will.)

The antiviral compound is micronized and dispersed in the molten suppository base (at 50 ^° C.). It is cooled to 35 to 37 ^° C. and filled into suitable suppository molds.

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Claims (41)

Claims 1. Pharmaceutical agent containing a pharmaceutical carrier or a diluent and as active Material a 7,7-dimethyl [2,2,1jbicycloheptane, which is in the 1-position has a group R, where R is an amino or aminomethyl group, or a derivative thereof which is a basic Contains nitrogen atom, and / or a physiologically acceptable salt thereof, wherein the derivative is a compound wherein R is on the amino nitrogen atom and / or on the 1O carbon atom by one or more aliphatic, cycloaliphatic, araliphatic or aryl groups or, in the case of the amino group, substituted by a heterocyclic group wherein the nitrogen atom of the amino group forms part of the heterocyclic ring, or, in the case of an N-substituted one Aminomethyl group, through an oxo group on the 10 carbon atom is substituted. 2. "Agent according to claim 1, characterized in that R is substituted with a CL _ / - alkyl, alkenyl or alkynyl group, which can be unsubstituted or substituted, with an amino, imino, hydroxy, thiol group, with an esterified or etherified hydroxyl or thiol group or, if a basic group is also present on the group, with an oxo group in the α-position, based on the 1- or 10-nitrogen atom, a CUg cycloalkyl group, a monocyclic group Aralkyl, aralkenyl or aralkynyl group, a phenyl group or a 5- or 6-membered heterocyclic aryl group or wherein the nitrogen atom of R forms part of a 4- to 8-membered heterocyclic ring which is unsubstituted or can be substituted by a C1-6 alkyl group. 3 · Agent according to claim 1 in dosage unit form. 4. The composition of claim 3 wherein each dosage unit contains 0.05 g to 4 g of active material. AO 9 8 3 9/1 016 5. Composition according to claim 3 »wherein each dosage unit contains 0.025 g to 4 g of active material. 6. Agent according to one of claims 1 to 4, which is suitable for administration as a nasal spray or nasal drops or in the form of an aerosol for inhalation. 7. Agent according to one of claims 1 to 4 or 6, wherein R is an amino or substituted amino group. 8. Agent according to one of claims 1 to 4 or 6, wherein R represents an aminomethyl or substituted aminomethyl group. 9. Composition according to claim 1, wherein the nitrogen atom of R is part of a heterocyclic ring which contains 4 to 8 ring members and which is formed by a hydroxy or C ^^ Q cycloalkyl group or which is fused to a second ring, or where R is substituted by a mono- or dialkylamino (C.i g) -alkyl group is substituted. 10. Composition according to claim 7, wherein R is a mono- or dialkylamino group or represents a group in which the nitrogen atom is part of a 5- or 6-membered heterocyclic Is a ring that may contain a second heteroatom. 11. Means according to claim 8, wherein R is an aminomethyl, mono- or dialkyl or alkenylaminomethyl or 1-aminoethyl group or wherein the nitrogen atom of R forms part of a 6- or 6-membered heterocyclic ring which is a may contain second heteroatom. 12. Means according to claim 1, wherein R is an aminomethyl group or the monomothyl, monoethyl, monoallyl, mono-n-butyl, Dimethyl or diethylamino substituted derivatives thereof, a 4-methylpiperazinomethyl, morpholinomethyl, 4098 3 9/101 6 ~ ³⁸ ~ 241349 2 Means piperidinomethyl or 1-aminoethyl group. 13. Agent according to claim 1, wherein R is an amino, methylamine? -, Means ethylamino or dimethylamino group. 14. Agent according to claim 1, wherein R is an isoindolinomethyl group. 15. 7,7-Dimethyl [2.2.1] bicycloheptanes, which are described in the 1-position contain a group, and the physiologically acceptable Salts thereof, wherein R is an amino or aminomethyl group containing a basic nitrogen atom and on the amino nitrogen atom and / or on the 1O carbon atom is substituted by one or more aliphatic, cycloaliphatic, araliphatic or aryl groups or, im Case of the amino group, by a heterocyclic group in which the nitrogen atom of the amino group is part of a heterocyclic group Is ring, or in the case of an N-substituted amino group, is substituted by an oxo group on the 10-carbon atom. 16. Compounds according to claim 15, wherein R is replaced by a CL _ / - alkyl, alkenyl or alkynyl group, which can be substituted or unsubstituted by a Amino, imino, hydroxy, thiol group, an esterified or etherified hydroxyl or thiol group or (if a basic group is also attached to the Group is present) an oxo group in α-position, based on the R nitrogen atom, a CUg cycloalkyl group, a monocyclic aralkyl, aralkenyl or aralkynyl group, a Phenyl group or a 5- or 6-membered heterocyclic aryl group is substituted, or wherein the nitrogen atom of R is part of a 4- to 8-membered heterocyclic ring which may be unsubstituted or by a C, g-alkyl group can be substituted. 17. Compounds according to claim 15, wherein R is a substituted amino group. 409839/1016 -39- 2410Λ92 18. Compounds according to claim 15, wherein R is a substituted aminomethyl group. 19. Compounds according to claim 15, wherein the nitrogen atom of R forms part of a heterocyclic ring having 4 to 8 ring members, which by a hydroxy or C, _ ₁₀ cycloalkyl group is substituted or is fused to a second ring, or wherein R by a mono- or dialkylamino group is substituted. 20. Compounds according to claim 17 or 18, wherein R is a group in which the nitrogen atom is part of a 5- or 6-membered heterocyclic ring which may contain a second heteroatom. 21. Compounds according to claim 15, wherein R is a mono- or dialkyl or alkenylaminomethyl or 1-aminoethyl group or wherein the nitrogen atom of R is part of a 5- or 6-membered heterocyclic ring which is a second May contain heteroatom. 22. Compounds according to claim 15, wherein R is a monomethyl, Monoethyl, dimethyl, diethyl, monoallyl or mono-n-butylaminomethyl group or a 4-methylpiperazinomethyl, Morpholinomethyl, piperidino-methyl or 1-aminoethyl group means. 23. Compounds according to claim 15, wherein R is an isoindolinomethyl group means. 24. Compounds according to claim 15, wherein R is a methyl, ethyl or dimethylamine group. 25.. Compounds according to claim 15 which contain a non-basic N-substituted 1-carbonamide group. 26. Process for the preparation of a compound according to claim 15, characterized in that one 409839/1016 - 4 ° - 2410A92 (A) when the group R contains a methylene group in the α-position, based on the nitrogen atom, the corresponding amide reduced, (b) when 'R is a methylamino group, one Ester of the corresponding carboxyamino compound reduced, (c) when R is a methylamino group, that corresponding amine reductively methylated, (d) when the nitrogen atom of R is connected by a double bond to an aliphatic or araliphatic substituent is bound, the corresponding amine condenses with an aldehyde or ketone, (e) when the nitrogen atom of R is part of a 1,3> 5-hexahydrotriazine ring forms a compound in which the amino group of R is unsubstituted with formaldehyde implements, (f) when R is an aminomethyl group in which one of the hydrogen atoms on the methyl carbon atom is substituted, which reduces ketoxime accordingly, (g) if the nitrogen atom contains an aryl substituent, the corresponding amine reacts with a benzyne, (h) if the nitrogen atom of R is replaced by an aliphatic, substituted cycloaliphatic or araliphatic group is, reacts the corresponding amine with a compound of the formula R ^ X, wherein R ^ is an aliphatic, cycloaliphatic or araliphatic group and X is an easily eliminable group, (i) when the nitrogen atom of R forms part of a heterocyclic ring, one is a compound after Claim 15 »wherein the nitrogen atom of R is replaced by a hydroxy alkyl group containing at least 3 carbon atoms and which has an eliminable group, is substituted, cyclized, (j) when R denotes an aminomethyl group in which the methyl group is substituted, the correspondingly substituted one Nitromethyl compound reduced, 409839/1016 (k) when the nitrogen atom of R is replaced by an aminoacyl group is substituted, reacts a corresponding haloacyl compound with ammonia or an amine, (l) when the nitrogen atom of R forms part of a heterocyclic ring, one is the corresponding unsubstituted Amine with a compound which contains two easily eliminable substituents, reacts, or (m) when the nitrogen atom of R is substituted by an aliphatic or araliphatic group, the corresponding compound in which the nitrogen atom is bonded to the group via a double bond is reduced. 27. The method according to claim 26, characterized in that a compound according to claim 17 according to a method according to claim 26 (a), (b), (c), (d) or (g) is produced. 28. The method according to claim 26, characterized in that a compound according to claim 18 according to a method according to claim 26 (a) by reduction of the corresponding 1-carbonamide or according to a method according to claim 26 (d) or (f) is produced. 29. Process for the preparation of a compound according to claim 25, characterized in that the corresponding Reacts 1-carboxylic acid or a reactive derivative thereof with a primary or secondary amine. 30. Means as described in example Λ. 31. Means as described in Examples B to G. 32. A compound according to claim 15, prepared as described in Examples 8-17. 33. A compound according to claim 15, prepared as in the Examples 18 or 19 described. 409839/1016 34. A compound according to claim 15, prepared as described in Examples 20-30. 35 · A method for producing a compound according to claim 15, carried out as described in Examples 8-17. 36. A process for the preparation of a compound according to claim 15 carried out as described in Examples 18 or 19. 37. A process for the preparation of a compound according to claim 15 carried out as described in Examples 20 to 30. 38. A compound according to claim 25, prepared as described in Examples 1 to 7. 39 · A method for producing a compound according to claim 25, carried out as described in Examples 1-7. 40. A compound produced according to a method according to any one of claims 26 to 29, 35 to 37 or 39. 41. A method for treating viral infections in animals including humans, characterized in that an agent according to claim 1 is administered to the animal or human. 409839/1016